DESCRIPTION: A central question to better understanding the pathogenesis of HIV infection is how memory CD4 T cells are infected and progressively depleted by HIV. Little is currently known about the impact of HIV infection on CD4 T cells of different pathogen or antigen specificities. Exploring this area is important for better understanding of the timing of different opportunistic infections in AIDS patients. In addition, identification of a functional population o vaccine-specific CD4 T cells that is resistant to HIV is critical for HIV vaccine design. We have established a novel system for studying the susceptibility of antigen-specific CD4 T cells to HIV, and have found that different antigen-specific CD4 T cells manifest marked differences in susceptibility to HIV infection. Our preliminary data show that compared to CD4 T cells specific to tetanus toxoid (TT) and Candida albicans (Candida), which are permissive to HIV, cytomegalovirus (CMV)-specific CD4 T cells are highly resistant to both R5 and X4 HIV with post-entry HIV restriction. Our microarray analysis identified a novel viral RNA sensor, IFIT1 that is highly upregulated in CMV-specific CD4 T cells. Of importance, in our ongoing experiments, we show that over-expression of IFIT1 significantly inhibits HIV infection in A3R5 CD4 T cell line. Based on data already generated, we hypothesize that IFIT1 can inhibit HIV infection in human primary CD4 T cells and differential expression of IFIT1 regulates the permissiveness of antigen-specific CD4 T cells to HIV. We further propose to extend the novel system and observations to clinical HIV vaccine studies. Preferential infection of vaccine-generated CD4 T cells by HIV reduces the efficiency of vaccine-induced immunity. Our hypothesis is that a protective HIV vaccine would induce a type of vaccine-specific CD4 T cells that are not readily susceptible to HIV, and that different candidate HIV vaccines (e.g. different vectors) induce distinct phenotypes of vaccine-specific CD4 T cells that may significantly impact their sensitivities to HIV. We will test peripheral blood mononuclear cell samples from three completed HIV vaccine trials: RV144 (ALVAC), RV158 (MVA) and IPVC001 (Ad26). Our hypotheses will be addressed in 2 Specific Aims: 1) To determine the role of IFIT1 in regulating the susceptibility of human antigen-specific CD4 T cells to HIV and to further explore the mechanisms for inhibition of HIV by IFIT1; 2) To investigate the susceptibilities of different HIV vaccine-induced, antigen-specific CD4 T cells to HIV infection and the associated phenotypes in HIV vaccine trials. The proposed studies are exploratory, but expected to provide new insights to: 1) understand the mechanisms for the persistence of CMV-specific T cell immunity in AIDS patients; 2) identify a novel anti-HIV molecule with previously unidentified inhibitory mechanisms/pathways that could lead to the development of novel HIV therapies; 3) better understand the quality of vaccine-generated CD4 T cell immunity and to provide proof of concept knowledge on whether and how to induce functional, HIV-resistant CD4 T cells by an HIV vaccine.